Compositions comprising lipophilic extracts of Zingiber officinale and Echinacea angustifolia for the prevention and treatment of gastro-oesophageal reflux and chemotherapy-induced emesis

ABSTRACT

The present invention relates to compositions consisting of a combination of lipophilic extracts of  Zingiber officinale  and  Echinacea angustifolia , obtained by extraction with carbon dioxide under supercritical conditions, which are useful for the prevention and treatment of oesophageal reflux and chemotherapy-induced emesis.

This application is a U.S. national stage of PCT/EP2010/000,204 filed on

Jan. 15, 2010 which claims priority to and the benefit of ItalianApplication No. MI200,9000,049 filed on Jan. 20, 2009, the contents ofwhich are incorporated herein by reference.

SUMMARY OF THE INVENTION

The present invention relates to compositions consisting of anassociation of lipophilic extracts of Zingiber officinale and Echinaceaangustifolia, which are useful for the prevention and treatment ofoesophageal reflux and chemotherapy-induced emesis.

PRIOR ART

Cancer of the gastrointestinal tract is the second most common form ofcancer, and the second-highest cause of death when this area isaffected. Oesophagus and stomach cancer are not very common in theindustrialised countries, but are extremely lethal.

A number of contributory causes have been identified for these twotumours, such as abuse of spirits, often combined with smoking, anitrate-rich diet, and/or products or habits that break the mucusbarrier in the stomach and oesophagus. Following examination of eatinghabits and deficiencies of some trace elements in populations fromdifferent continents (Plummer-Vinson and Paterson-Kelly syndromes),attempts have been made to prevent the onset of carcinoma of the stomachand oesophagus due to said contributory causes by modifying eatinghabits and lifestyles, and using medicinal or diet products. Althoughmany of said contributory causes have been eliminated, the globalincidence has increased because of an increase in the number of peoplesuffering from gastro-oesophageal reflux, often associated with dietand/or hiatus hernia, which is one of the main causes of oesophagealtumours. Adenocarcinoma is manifested by dysplastic columnar epitheliumin the distal part of the oesophagus, nearly always in the presence ofchronic reflux and gastric metaplasia of the epithelium (Barrett'soesophagus), which are common in obese individuals, and becomesmalignant in over 50% of cases.

It is therefore very important to reduce the incidence of this disorder.

Research is consequently oriented towards drugs able to reduce reflux,especially by modifying gastric emptying. In particular, researchers areattempting to develop well-tolerated natural prokinetics, as thepotential drug will have to be taken chronically for many years on apreventive basis, or discontinuously, depending on digestiverequirements.

However, many drugs which have been used recently to modify gastricvoiding present serious side effects affecting the CNS or have acarcinogenic action, and have therefore either been, or are about to be,withdrawn from the market. Gastro-oesophageal reflux is currentlytreated with a cocktail of drugs such as proton pump inhibitors(ranitidine, -prazoles or simple antacids), enzymes, various digestivedrugs, and prokinetics such as domperidone. However, long-term use ofproton pump inhibitors often leads to major digestive problems.

Research is consequently now oriented towards new therapeuticapproaches.

DESCRIPTION OF THE INVENTION

It has now been found that a combination comprising lipophilic extractsof Zingiber officinale and Echinacea angustifolia, both prepared byextraction with carbon dioxide under supercritical conditions, has asurprising prokinetic and anti-emetic activity, leaving the digestivefunction unchanged and eliminating the feeling of heaviness of thestomach and nausea which are contributory causes of oesophageal reflux;it is therefore useful in the prevention and treatment of oesophagealreflux and chemotherapy-induced emesis.

The invention therefore relates to compositions containing:

a) a lipophilic extract of Zingiber officinale, and

b) a lipophilic extract of Echinacea angustifolia,

for the prevention and treatment of oesophageal reflux andchemotherapy-induced emesis.

More specifically, according to the invention, the lipophilic extract ofEchinacea angustifolia will be prepared by extraction with carbondioxide under supercritical conditions as reported in patent EP 464298filed by the applicant. The lipophilic extract of Zingiber officinalecan also be extracted under the same conditions, starting with thepulverised roots.

The roots and rhizomes of ginger (Zingiber officinale), treated invarious ways, are used, especially in Asia and the Middle East, asspices and in traditional medicine to treat indigestion, flatulence,diarrhoea, coughing, and, to a lesser extent, to protect the mucousmembranes, against inflammation, to treat urinary incontinence, etc.

The active components present in the lipophilic extract of Zingiberofficinale mainly consist of gingerols (generally present inconcentrations ranging between 10 and 15%), which possess ananti-dyspeptic, anti-nausea and anti-vomiting activity, and are usefulfor the treatment of motion sickness, belching, indigestion, colic,vomiting, dyspepsia and stomach and colon pain. However, recent clinicaltrials have demonstrated that the lipophilic extract of Zingiberofficinale prepared by traditional methods presents low activity in viewof the well-known chemical instability of gingerols; the USpharmacopoeia therefore recommends a complete review of the propertiesattributed to the plant due to the lack of convincing evidence. Thegingerols contained in the lipophilic extract of Zingiber officinaleprepared by traditional methods break down rapidly, giving rise to aseries of compounds, such as shogaol and other products of oxidation,which are devoid of efficacy. These conflicting data are partly due tothe instability of the active components in the extracts normally used.However, the extract used in the present invention is a lipophilicextract, stabilised and prepared with carbon dioxide under well-definedsupercritical conditions.

The lipophilic extract of the roots and aerial parts of Echinaceaangustifolia is characterised by the presence of isobutylamides ofpolyunsaturated acids with analgesic and anti-inflammatory properties,anti-nausea and anti-vomiting activity, associated with theirinteraction with the cannabinoid receptors. The combination according tothe invention possesses a surprisingly marked prokinetic andanti-dyspeptic effect, leaving the digestive function unchanged andeliminating the feeling of heaviness in the stomach and nausea which arecontributory causes of oesophageal reflux. This combination cantherefore be usefully employed in the prevention and treatment ofoesophageal reflux and chemotherapy-induced emesis.

The compositions according to the invention increase gastric emptying, ahighly potent and entirely unexpected effect, as said activity is notdemonstrable for the individual components in any of the patientstreated. Indeed, as stated above, it has been observed that theadministration of alkylamides of Echinacea angustifolia slows gastricand intestinal voiding rather than promoting it.

According to a preferred aspect, the compositions according to theinvention will contain the two components within the following weightintervals:

a) lipophilic extract of Zingiber officinale: 1 to 25 mg; and

b) lipophilic extract of Echinacea angustifolia: 1 to 10 mg.

According to a particularly preferred aspect, the compositions willcontain the two components in the following quantities by weight:

a) lipophilic extract of Zingiber officinale: 12.5 mg; and

b) lipophilic extract of Echinacea angustifolia: 5 mg.

According to a preferred aspect, the compositions according to theinvention will contain a lipophilic extract of Echinacea angustifoliaprepared according to the process described in EP 464298, characterisedby a 25-50% content in isobutylamides, in particulardodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide.

According to a preferred aspect, the lipophilic extract of Zingiberofficinale and the lipophilic extract of Echinacea angustifolia will beformulated in vegetable oils rich in ω3/ω6 polyunsaturated fatty acids,such as evening primrose oil.

According to a further aspect, the compositions according to theinvention may be administered together with other substances having auseful or complementary activity.

The doses which have proved active in man are 1 to 25 mg of lipophilicextract of Zingiber officinale and 1 to 10 mg of lipophilic extract ofEchinacea angustifolia per dose; more particularly, 12.5 mg oflipophilic extract of Zingiber officinale and 5 mg of lipophilic extractof Echinacea angustifolia per dose, to be taken with every main meal orotherwise adapted to the disorder to be treated.

The compositions according to the invention will be formulated accordingto conventional methods, such as those described in “Remington'sPharmaceutical Handbook”, Mack Publishing Co., N.Y., USA. In particular,the compositions according to the invention will be formulated accordingto conventional formulation techniques for lipophilic ingredientsintended for oral administration, mainly as sublingual tablets or softgelatin or cellulose capsules for oils designed to disperse rapidly inthe stomach. The lipophilic form uses oils rich in ω-3 fatty acids,which promote rapid absorption of the active ingredient, to disperse theactive components. Examples of oral formulations are tablets, dragées,soft and hard gelatin capsules, and cellulose capsules.

The following examples further illustrate the invention.

EXAMPLE 1 Soft Gelatin Capsules

Unit composition:

Lipophilic extract of Zingiber officinale 12.5 mg  Lipophilic extract ofEchinacea angustifolia  5 mg Soya lecithin  10 mg Evening primrose oil150 mg

EXAMPLE 2 Hard Gelatin Capsules

Unit composition:

Lipophilic extract of Zingiber officinale 12.5 mg   Lipophilic extractof Echinacea angustifolia 5 mg Soya lecithin 10 mg  Microcrystallinecellulose 200 mg  Maize starch 50 mg  Magnesium stearate 2 mg Silicondioxide 2 mg

1. A method of increasing gastric emptying or treating esophageal reflux and chemotherapy-induced emesis comprising: administering an effective amount of a composition comprising: a) lipophilic extract of Zingiber officinale, and b) lipophilic extract of Echinacea angustifolia, to a patient in need thereof; and increasing gastric emptying in said patient or treating esophageal reflux and chemotherapy-induced emesis in said patient.
 2. The method of claim 1, wherein said effective amount is from 1 to 25 mg of said lipophilic extract of Zingiber officinale and from 1 to 10 mg of said lipophilic extract of Echinacea angustifolia per dose.
 3. The method of claim 2, wherein said effective amount is 12.5 mg of said lipophilic extract of Zingiber officinale and 5 mg of lipophilic extract of Echinacea angustifolia per dose. 